The aging process is characterized by a general decline in physiological functions that affects many tissues and increases the risk of death. In the present investigation using various substrates, the respiration rate was observed in young, middle-aged, and aged rats upon administration of carnitine (300 mg/kg body weight) and lipoic acid (100 mg/kg body weight). We observed that the rate of respiration, both State 3 and respiratory control ratio, decreased significantly in aged rats after using various substrates (except succinate). An increase in the State 4 respiration was observed in aged rats when beta-hydroxybutyrate as well as pyruvate and malate were used as substrates, whereas no change in the adenosine diphosphate/oxygen ratio ratio was observed. These changes were brought to normal levels upon cosupplementation of carnitine and lipoic acid. Thus, this study provides evidence for the role of carnitine and lipoic acid in alleviating the age-related decline in mitochondrial respiratory activity.